The eye lens not only provides and excellent model system for development, aging, and protein structure and interaction, but is important clinically for vision. A better understanding of cataractogenesis will come through an understanding of the molecular components of the lens of the eye and the ways in which lesions of these components are manifested, structurally and functionally, as opacity of the lens. Currently, several different genetic congenital cataracts are being studied by linkage analysis, physical mapping, mutational screening, and expression in transgenic mice and in vitro. In addition, it is apparent that hereditary lesions that mimic or contribute additively to environmental stress known to cause cataracts might be candidate genes for causing age related cataracts. Age related cataracts are being studied by association analysis and sequencing of candidate genes followed by molecular genetic investigation of wild type and mutant gene structure and function. The work in this project is designed to specifically concentrate on congenital and complex hereditary cataracts and to take full advantage of molecular technology developed for linkage analysis and protein structural and functional studies. Lens crystallins comprise over 90% of the soluble protein of the lens and are heavily modified in most cataracts. The effects that specific modifications of beta and gamma-crystallin structure produce on crystallin functions, such as stability and formation of macromolecular aggregates, are being studied using SF9 cells or bacteria transformed with coding sequences of normal and modified beta A3/A1-, B1, B2- and gammaS-crystallin genes. Regions of the beta-crystallin molecule of special interest include the amino and carboxy terminal arms, the connecting peptide and the Greek key motifs of the core domains. In addition, new loci and genes associated with age related cataract are being identified, and the characteristics of mutations leading to congenital Mendelian or age related complex cataracts are being studied. Pathways of cataractogenesis, including the UPR and apoptosis are being explored. Finally, the biological activity of crystallins in extralenticular systems are being investigated.